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Synthesis of Bioactive Analogues of Marasmane Dialdehydes

Röme, Daniel LU (2005)
Abstract (Swedish)
Popular Abstract in Swedish

Transformationen av läkemedel till "pro-drugs" är ett lockande koncept där man tillåts förändra en förenings kemiska och fysikaliska egenskaper utan att ändra den aktiva molekylens struktur. Vilken förening som helst kan i princip omformas till en "pro-drug". Många naturprodukter besitter egenskaper som är potentiellt intressanta för behandling av sjukdom men är svåra att implementera i sig själva. Marasmandialdehyderna isovelleral och marasminsyra är två naturprodukter av denna typ.



De två dialdehyderna är sekundära metaboliter isolerade från olika svampar (t.ex. isovelleral från Lactarius vellerus och marasminsyra från svamparten Marasmius). Ett flertal biologiska karaktärer... (More)
Popular Abstract in Swedish

Transformationen av läkemedel till "pro-drugs" är ett lockande koncept där man tillåts förändra en förenings kemiska och fysikaliska egenskaper utan att ändra den aktiva molekylens struktur. Vilken förening som helst kan i princip omformas till en "pro-drug". Många naturprodukter besitter egenskaper som är potentiellt intressanta för behandling av sjukdom men är svåra att implementera i sig själva. Marasmandialdehyderna isovelleral och marasminsyra är två naturprodukter av denna typ.



De två dialdehyderna är sekundära metaboliter isolerade från olika svampar (t.ex. isovelleral från Lactarius vellerus och marasminsyra från svamparten Marasmius). Ett flertal biologiska karaktärer är associerade med dessa strukturer, t.ex. bakterie-, svamp- och tumörhämmande egenskaper såväl som cytotoxicitet och mutagenisitet. Det finns ett flertal totalsynteser av båda naturprodukterna och även vissa försök att syntetiskt påverka deras aktivitet.



Två analoger av dessa naturprodukter har syntetiserats i den här avhandlingen för att studera möjligheten att påverka deras aktiviteter syntetiskt, typiskt genom att ändra metyleringsgrad samt ringsystem. Vi fann att den tridemetylerade analogen av isovelleral hade 4 till 11 gånger högre cytotoxicitet jämfört med isovelleral och av samma storlek som den mest potenta kommersiellt tillgängliga cytostatikan. Fortsättningsvis utfördes teoretiska och experimentella studier av de reaktionsmekanismer med vilka dessa dialdehyder tros utöva sin aktivitet. Möjligheten att omvandla de nya såväl som de gamla strukturerna till "pro-drugs" undersöktes omsorgsfullt. Vi fokuserade i huvudsak på utvecklingen av "pro-drugs" för behandling av cancer och tillämpning som miljövänliga bekämpningsmedel. Det har redan uppnåtts lovande resultat för den senare tillämpningen vad beträffar bekämpning av angrepp av svampen Magnaporthe grisea på ris.



Vi har i den här avhandlingen blottställt en ny plattform för behandling och bekämpning av sjukdomar och parasiter med derivat av isovelleral och marasminsyra såväl som med naturprodukterna själva i ett "pro-drug"-koncept. (Less)
Abstract
The modification of drugs into pro-drugs is an attractive concept allowing you to tweak the chemical and physical properties of a drug without changing the original structure of the active compound. In principle, any compound possessing a preferred biological activity can be transformed into a pro-drug. Many natural products harbor qualities that are potentially interesting as drugs but difficult to implement per se. The marasmane dialdehydes, isovelleral and marasmic acid are two such compounds which are investigated in thesis.



These dialdehydes are secondary metabolites isolated from several different fungi (e.g. isovelleral from Lactarius vellerus and marasmic acid from the Marasminus species). There are many... (More)
The modification of drugs into pro-drugs is an attractive concept allowing you to tweak the chemical and physical properties of a drug without changing the original structure of the active compound. In principle, any compound possessing a preferred biological activity can be transformed into a pro-drug. Many natural products harbor qualities that are potentially interesting as drugs but difficult to implement per se. The marasmane dialdehydes, isovelleral and marasmic acid are two such compounds which are investigated in thesis.



These dialdehydes are secondary metabolites isolated from several different fungi (e.g. isovelleral from Lactarius vellerus and marasmic acid from the Marasminus species). There are many biological characteristics associated with these structures, e.g. antifeedant, antibacterial, antifungal, antitumor, cytotoxic and mutagenic activities. Several total syntheses of both natural products have been presented along with limited efforts to synthetically modify their activities.



In this thesis, two analogues of these dialdehydes were prepared to further study the possibility to enhance their activities by synthetically modifying these structures. i.e. altering methylation patterns and changing ring systems. We found that the cytotoxicity of the tridemethylated analogue was between 4 and 11 times higher in our assay in comparison with that of isovelleral, and of the same magnitude as that of most potent commercial anti-tumor agents. Furthermore, we have performed theoretical and experimental investigations into their reactivity and reaction mechanisms. The possibility to transform these novel structures along with the original compounds into potential pro-drugs has been extensively investigated. We have focused our attention to the development of pro-drugs in particular related to cancer and environmentally friendly pesticides. In case of the latter application, promising results have already been shown towards the control of the rice blast disease caused by Magnaporthe grisea.



Thus, this work expose a novel platform for targeting diseases using derivatives of isovelleral and marasmic acid, as well as the natural products, in a pro-drug concept. (Less)
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author
supervisor
opponent
  • Docent Unelius, Rikard, Kemi och biomedicinsk vetenskap, Högskolan i Kalmar
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Organisk kemi, Organic chemistry, Cancer, Enantioselective synthesis, Totalsynthesis, Semisynthesis, Cytotoxicity, Anti-tumor activity, Isovelleraloids, Marasmic acid, Marasmane dialdehydes, Isovelleral
pages
171 pages
publisher
Department of Organic Chemistry, Lund University
defense location
Room K:C, Centre for Chemistry and Chemical Engineering, Getingev 60, Lund Institute of Technology
defense date
2005-06-09 09:30
ISBN
91-628-6548-X
language
English
LU publication?
yes
id
33cd70c3-483f-417a-aa3f-5c27b0af1d69 (old id 545036)
date added to LUP
2007-10-13 13:09:21
date last changed
2016-09-19 08:45:10
@misc{33cd70c3-483f-417a-aa3f-5c27b0af1d69,
  abstract     = {The modification of drugs into pro-drugs is an attractive concept allowing you to tweak the chemical and physical properties of a drug without changing the original structure of the active compound. In principle, any compound possessing a preferred biological activity can be transformed into a pro-drug. Many natural products harbor qualities that are potentially interesting as drugs but difficult to implement per se. The marasmane dialdehydes, isovelleral and marasmic acid are two such compounds which are investigated in thesis.<br/><br>
<br/><br>
These dialdehydes are secondary metabolites isolated from several different fungi (e.g. isovelleral from Lactarius vellerus and marasmic acid from the Marasminus species). There are many biological characteristics associated with these structures, e.g. antifeedant, antibacterial, antifungal, antitumor, cytotoxic and mutagenic activities. Several total syntheses of both natural products have been presented along with limited efforts to synthetically modify their activities.<br/><br>
<br/><br>
In this thesis, two analogues of these dialdehydes were prepared to further study the possibility to enhance their activities by synthetically modifying these structures. i.e. altering methylation patterns and changing ring systems. We found that the cytotoxicity of the tridemethylated analogue was between 4 and 11 times higher in our assay in comparison with that of isovelleral, and of the same magnitude as that of most potent commercial anti-tumor agents. Furthermore, we have performed theoretical and experimental investigations into their reactivity and reaction mechanisms. The possibility to transform these novel structures along with the original compounds into potential pro-drugs has been extensively investigated. We have focused our attention to the development of pro-drugs in particular related to cancer and environmentally friendly pesticides. In case of the latter application, promising results have already been shown towards the control of the rice blast disease caused by Magnaporthe grisea.<br/><br>
<br/><br>
Thus, this work expose a novel platform for targeting diseases using derivatives of isovelleral and marasmic acid, as well as the natural products, in a pro-drug concept.},
  author       = {Röme, Daniel},
  isbn         = {91-628-6548-X},
  keyword      = {Organisk kemi,Organic chemistry,Cancer,Enantioselective synthesis,Totalsynthesis,Semisynthesis,Cytotoxicity,Anti-tumor activity,Isovelleraloids,Marasmic acid,Marasmane dialdehydes,Isovelleral},
  language     = {eng},
  pages        = {171},
  publisher    = {ARRAY(0x8866d88)},
  title        = {Synthesis of Bioactive Analogues of Marasmane Dialdehydes},
  year         = {2005},
}